RU2016104643A - BIOMARKERS FOR THE TREATMENT OF NEOPLASTIC DISEASES WITH THE APPLICATION OF METHODS TREATED AT ANDROGEN - Google Patents

BIOMARKERS FOR THE TREATMENT OF NEOPLASTIC DISEASES WITH THE APPLICATION OF METHODS TREATED AT ANDROGEN Download PDF

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RU2016104643A
RU2016104643A RU2016104643A RU2016104643A RU2016104643A RU 2016104643 A RU2016104643 A RU 2016104643A RU 2016104643 A RU2016104643 A RU 2016104643A RU 2016104643 A RU2016104643 A RU 2016104643A RU 2016104643 A RU2016104643 A RU 2016104643A
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androgen receptor
sample
response
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Дуглас ДЖЕЙКОБИ
Винсент НЬЯР
Амина ЗУБЕЙДИ
Карен ФЕРРАНТЕ
Ева КОРИ
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Токай Фармасьютикалз, Инк.
Юниверсити Оф Мэриленд, Балтимор
Юниверсити Оф Вашингтон
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Claims (54)

1. Способ лечения заболевания у нуждающегося в этом пациента, включающий:1. A method of treating a disease in a patient in need thereof, comprising: a. получение образца от указанного пациента,a. receiving a sample from the specified patient, b. определение того, присутствует ли в указанном образце измененная форма андрогенового рецептора; и,b. determining whether an altered form of the androgen receptor is present in said sample; and, c. если указанная измененная форма андрогенового рецептора присутствует, введение указанному субъекту фармацевтической композиции, содержащей терапевтически эффективное количество соединения формулы I,c. if said altered form of the androgen receptor is present, administering to said subject a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I,
Figure 00000001
Figure 00000001
 или фармацевтически приемлемой соли, N-оксида, активного метаболита, пролекарства или сольвата указанного соединения; где R1 представляет собой Н или ацетил; и R2 представляет собой бензимидазол.or a pharmaceutically acceptable salt, N-oxide, active metabolite, prodrug or solvate of the compound; where R 1 represents H or acetyl; and R 2 represents benzimidazole. 2. Способ, включающий этап2. The method comprising the step введения терапевтического средства субъекту, который страдает раком предстательной железы и экспрессирует измененную форму андрогенового рецептора, указанное терапевтическое средство включает введение агента, выбранного из группы, состоящей из соединения формулы I:administering a therapeutic agent to a subject that suffers from prostate cancer and expresses an altered form of the androgen receptor, said therapeutic agent comprises administering an agent selected from the group consisting of a compound of formula I:
Figure 00000002
Figure 00000002
 или фармацевтически приемлемой соли указанного соединения; где R1 представляет собой Н или ацетил; и R2 представляет собой бензамидазол.or a pharmaceutically acceptable salt of said compound; where R 1 represents H or acetyl; and R 2 represents benzamidazol. 3. Способ по п. 2, отличающийся тем, что в образце от субъекта обнаружена измененная форма андрогенового рецептора.3. The method according to p. 2, characterized in that a modified form of the androgen receptor is found in the sample from the subject. 4. Способ по п. 3, отличающийся тем, что указанный образец выбран из группы, состоящей из цельной крови, сыворотки, плазмы, ткани, семенной жидкости, клетки, биоптата, слизистой, кала, кости, зубов, мазка из носа, или горла, или щеки, мочи, кожи, слез, биоптата органа, биоптата опухоли или опухолевой ткани, циркулирующих опухолевых клеток, экзосом из первичной опухоли или из метастатической ткани, и комбинаций перечисленных образцов.4. The method according to p. 3, characterized in that the specified sample is selected from the group consisting of whole blood, serum, plasma, tissue, seminal fluid, cells, biopsy, mucous membranes, feces, bones, teeth, nasal swab, or throat or cheeks, urine, skin, tears, organ biopsy, biopsy of a tumor or tumor tissue, circulating tumor cells, exosomes from a primary tumor or from metastatic tissue, and combinations of these samples. 5. Способ по п. 3, отличающийся тем, что указанный образец представляет собой обработанный образец.5. The method according to p. 3, characterized in that said sample is a processed sample. 6. Способ по п. 2, отличающийся тем, что указанный образец представляет собой образец, обогащенный циркулирующими опухолевыми клетками (ЦОК).6. The method according to p. 2, characterized in that said sample is a sample enriched with circulating tumor cells (CSCs). 7. Способ по п. 2, отличающийся тем, что рак предстательной железы устойчив к кастрации.7. The method according to p. 2, characterized in that the prostate cancer is resistant to castration. 8. Способ по п. 2, отличающийся тем, что указанный субъект был подвергнут химической кастрации или хирургической кастрации.8. The method according to p. 2, characterized in that the said subject was subjected to chemical castration or surgical castration. 9. Способ по п. 2, отличающийся тем, что рак предстательной железы устойчив к антагонисту андрогенового рецептора.9. The method of claim 2, wherein the prostate cancer is resistant to an androgen receptor antagonist. 10. Способ по п. 9, отличающийся тем, что указанный антагонист андрогенового рецептора представляет собой энзалутамид, или бикалутамид, или ARN-509.10. The method of claim 9, wherein said androgen receptor antagonist is enzalutamide, or bicalutamide, or ARN-509. 11. Способ по п. 2, отличающийся тем, что рак устойчив к терапии ингибитором CYP17.11. The method according to p. 2, characterized in that the cancer is resistant to therapy with a CYP17 inhibitor. 12. Способ по п. 11, отличающийся тем, что указанный ингибитор CYP17 представляет собой абиратерон.12. The method of claim 11, wherein said CYP17 inhibitor is abiraterone. 13. Способ по п. 2, отличающийся тем, что рак устойчив к терапии таксаном.13. The method according to p. 2, characterized in that the cancer is resistant to taxane therapy. 14. Способ по п. 2, отличающийся тем, что рак является андрогензависимым.14. The method according to p. 2, characterized in that the cancer is androgen-dependent. 15. Способ по п. 2, отличающийся тем, что этап введения включает введение суточной дозы в рамках диапазона от приблизительно 0,03 до приблизительно 60 мг/кг массы тела.15. The method according to p. 2, characterized in that the introduction phase includes the introduction of a daily dose within the range of from about 0.03 to about 60 mg / kg of body weight. 16. Способ по п. 2, отличающийся тем, что этап введения включает введение приблизительно 2,550 мг ежедневно.16. The method according to p. 2, characterized in that the introduction phase includes the introduction of approximately 2.550 mg daily. 17. Способ по п. 2, отличающийся тем, что этап введения включает пероральное введение.17. The method according to p. 2, characterized in that the introduction phase includes oral administration. 18. Способ по п. 2, отличающийся тем, что этап введения включает введение в течение периода времени, достаточного для того, чтобы указанный субъект проявил ответ на терапию, указанный ответ представляет собой или включает изменение клинического или медицинского проявления, прогноза, симптомов, диагностических показателей, характерных признаков, выживаемости или исходов.18. The method according to p. 2, characterized in that the introduction phase includes the introduction for a period of time sufficient for the specified subject to respond to therapy, the specified response is or includes a change in clinical or medical manifestation, prognosis, symptoms, diagnostic indicators, traits, survival, or outcomes. 19. Способ по п. 18, отличающийся тем, что указанный ответ представляет собой или включает одно или более из перечисленного:19. The method according to p. 18, characterized in that the response is or includes one or more of the following: снижение уровня ПСА по сравнению с уровнем до лечения, уменьшение боли, улучшение качества жизни, которое оценивают по оценке самого пациента, изменение количества ЦОК, изменение характеристик ЦОК, выживаемость без прогрессирования заболевания, определенную по уровню ПСА, рентгенографическую выживаемость без прогрессирования заболевания и индукцию иммунного ответа на опухолевые антигены.a decrease in PSA compared with the level before treatment, a decrease in pain, an improvement in the quality of life, as assessed by the patient’s assessment, a change in the number of CTCs, a change in the characteristics of the CTC, survival without disease progression, determined by the level of PSA, radiographic survival without disease progression and immune induction response to tumor antigens. 20. Способ по п. 18, отличающийся тем, что выживаемость представляет собой общую выживаемость.20. The method according to p. 18, characterized in that the survival rate is the overall survival rate. 21. Способ по п. 18, отличающийся тем, что снижение уровня ПСА представляет собой максимальное снижение уровня ПСА по меньшей мере на 50%.21. The method according to p. 18, characterized in that the decrease in the PSA level is the maximum decrease in the PSA level by at least 50%. 22. Способ, включающий следующие этапы:22. The method comprising the following steps: а. определение статуса биомаркера, который представляет собой или включает измененную форму андрогенового рецептора в образце от субъекта, которого подвергли лечению заболевания предстательной железы, применяя некоторую схему but. determining the status of a biomarker, which is or includes an altered form of the androgen receptor in a sample from a subject who has been treated for prostate disease using some scheme лечения, при этом указанная схема лечения включает введение соединения формулы I:treatment, while the specified treatment regimen includes the introduction of a compound of formula I:
Figure 00000003
Figure 00000003
 или фармацевтически приемлемой соли указанного соединения; где R1 представляет собой Н или ацетил; и R2 представляет собой бензамидазол; иor a pharmaceutically acceptable salt of said compound; wherein R 1 is H or acetyl; and R 2 is benzamidazole; and b. сохранение или изменение схемы терапии в зависимости от определенного статуса биомаркера.b. maintaining or changing the treatment regimen depending on the specific status of the biomarker. 23. Способ, включающий этап23. The method comprising the step введения эффективного количества соединения формулы I:introducing an effective amount of a compound of formula I:
Figure 00000003
Figure 00000003
 или фармацевтически приемлемой соли указанного соединения популяции субъектов с утраченным С-концом AR.or a pharmaceutically acceptable salt of said compound of a population of individuals with a lost C-terminus of AR. 24. Способ по п. 23, отличающийся тем, что введение эффективного количества соединения формулы I позволяет получить ответ, который представляет собой или включает изменение клинического или медицинского проявления, прогноза, симптомов, диагностических показателей, характерных признаков, выживаемости или исходов.24. The method according to p. 23, characterized in that the introduction of an effective amount of a compound of formula I allows you to get a response that represents or includes a change in clinical or medical manifestation, prognosis, symptoms, diagnostic parameters, characteristic signs, survival or outcomes. 25. Способ по п. 24, отличающийся тем, что указанный ответ представляет собой или включает максимальный уровень ответа ПСА >50%, достигнутый в популяции.25. The method according to p. 24, characterized in that the response is or includes a maximum PSA response> 50% achieved in the population. 26. Способ по п. 24, отличающийся тем, что указанный ответ представляет собой или включает один или более из перечисленных ответов: снижение уровня ПСА по сравнению с уровнем до лечения, уменьшение боли, улучшение качества жизни, которое оценивают по оценке самого пациента, изменение количества ЦОК, изменение характеристик ЦОК, выживаемость без прогрессирования заболевания, определенную по уровню ПСА, рентгенографическую выживаемость без прогрессирования заболевания и индукцию иммунного ответа на опухолевые антигены.26. The method according to p. 24, characterized in that the response represents or includes one or more of the following answers: a decrease in the level of PSA compared to the level before treatment, a decrease in pain, an improvement in the quality of life, which is assessed by the patient’s assessment, change the number of CTC, changes in the characteristics of the CTC, survival without disease progression, determined by PSA level, radiographic survival without disease progression, and the induction of an immune response to tumor antigens. 27. Способ по п. 24, отличающийся тем, что указанный ответ представляет собой или включает повышение общей выживаемости.27. The method according to p. 24, characterized in that said response is or includes an increase in overall survival. 28. Способ, включающий следующие этапы:28. The method comprising the following steps: осуществление терапии антипролиферативным лекарственным средстовом субъекта, страдающего раком предстательной железы, который экспрессирует полноразмерный андрогеновый рецептор и/или один или более сплайсинговых вариантов андрогенового рецептора; при этомadministering an antiproliferative drug to a subject suffering from prostate cancer that expresses a full-sized androgen receptor and / or one or more splicing variants of the androgen receptor; wherein если в раковой опухоли экспрессируется один или более сплайсинговых вариантов андрогенового рецептора, то указанная терапия представляет собой или включает введение эффективного количества соединения формулы I:if one or more splicing variants of the androgen receptor is expressed in a cancerous tumor, then this therapy is or involves the administration of an effective amount of a compound of formula I:
Figure 00000004
Figure 00000004
 или фармацевтически приемлемой соли указанного соединения; где R1 представляет собой Н или ацетил; и R2 представляет собой бензамидазол; иor a pharmaceutically acceptable salt of said compound; where R 1 represents H or acetyl; and R 2 is benzamidazole; and если в раковой опухоли не экспрессируется сплайсинговый вариант, то указанная терапия представляет собой или включает введение терапевтического средства, выбранного из группы, состоящей из: соединения или фармацевтически приемлемой соли указанного соединения, кастрации, антагониста андрогенового рецептора, ARN-509, винклозолина, процимидона, линурона, метаболита ДДТ дихлордифенилдихлорэтилена (п,п'-ДДЕ), кетоконазола, фенитротиона, ди(н-бутил)фталата (ДБФ), диизобутилфталата (ДИБФ), бензилбутилфталата (ББФ), бис(2-этилгексил)фталата (ДЭГФ), ди(н-пентил)фталата (ДПФ), парабеновых сложных эфиров, 3,3'-дииндолилметана (ДИМ), шлемника байкальского, N-бутилбензолсульфонамида (НББС), атраровой кислоты, бикалутамида, флутамида, спиронолактона, ципротерона ацетата, финастерида, дутастерида, нилутамида и комбинаций перечисленных способов терапии.if a splicing variant is not expressed in a cancerous tumor, then said therapy is or includes the administration of a therapeutic agent selected from the group consisting of: a compound or a pharmaceutically acceptable salt of said compound, castration, androgen receptor antagonist, ARN-509, vinclozolin, procymidone, linuron metabolite of DDT dichlorodiphenyldichlorethylene (p, p'-DDE), ketoconazole, phenitrothione, di (n-butyl) phthalate (DBP), diisobutylphthalate (DIBP), benzylbutylphthalate (BBP), bis (2-ethylhexyl) (n-pentyl) phthalate (DFT), paraben esters, 3,3'-diindolylmethane (DIM), Scutellaria baicalensis, N-butylbenzenesulfonamide (NBS), atrara acid, bicalutamide, flutamide, spironolactone, cyproterteride acetate, fin nilutamide and combinations of the listed methods of therapy. 29. Способ, включающий следующие этапы:29. The method comprising the following steps: введение терапевтического средства субъекту, который страдает раком предстательной железы и экспрессирует AR-V7, указанная терапия включает введение соединения формулы I:administering a therapeutic agent to a subject who suffers from prostate cancer and expresses AR-V7, said therapy includes administering a compound of formula I:
Figure 00000004
Figure 00000004
 или фармацевтически приемлемой соли указанного соединения, где R1 представляет собой Н и R2 представляет собой бензамидазол.or a pharmaceutically acceptable salt thereof, wherein R 1 represents H and R 2 represents benzamidazol.
RU2016104643A 2013-08-12 2014-08-12 BIOMARKERS FOR THE TREATMENT OF NEOPLASTIC DISEASES WITH THE APPLICATION OF METHODS TREATED AT ANDROGEN RU2016104643A (en)

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US201361865038P 2013-08-12 2013-08-12
US61/865,038 2013-08-12
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